Recent evidence from two independent lines of investigation has merged to suggest that neoplasia results from the abnormal activation of a relatively small number of cellular genes. Certain retroviruses contain transduced cellular genes which infer transforming properties to the retrovirus. The retroviruses containing thee cellular sequences in their genome can induce tumors in animals or transform cells in vitro. Subsequent studies have established that proto-oncogenes can also be activated as oncogenes in naturally occurring tumor cells by mechanisms completely independent of retroviral involvement. These genetic alterations range from point mutations to gross DNA rearrangements such as translocation and gene amplification. We have initiated studies to investigate oncogene activation and expression in spontaneous and chemical-induced tumors in rodents. Results to date have characterized activated oncogenes in spontaneous tumors of the mouse lung and liver as well as chemically induced tumors in rats and mice. These studies have provided data which show that oncogene activation in spontaneous tumors is different, in some cases, from that observed in chemically induced tumors, thereby providing a possible approach to substantially increase sensitivity of rodent bioassays for detection and classification of carcinogens according to mechanism of action. Novel mutations in the ras family of oncogenes, such as mutations in the 117th codon of Ha-ras, have been identified in primary tumors, and several potentially new transforming genes have been detected. Relationships between biological "hot spots" for the gene activation and sequence specificity for DNA binding of several carcinogens is also being investigated. Characterization of oncogene activation in different tumor types or the same tumor type in different animal species suggest that activation of a proto-oncogene is a common pathway for tumor induction for some chemicals. These approaches may enable us to more accurately estimate risk of cancer in humans exposed to specific classes of carcinogens.